Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/18—Iodine; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/02—Local antiseptics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/20—Antivirals for DNA viruses
  • A61P31/22—Antivirals for DNA viruses for herpes viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to a mixture based on halogenated compounds for the treatment of viral, bacterial, parasitic, fungal infections or by unconventional Transmissible Agents (NCTAs) but also chronic, progressive or acute inflammations for immunological treatments.
• the mixture of the invention is particularly useful as an antiseptic for local use.
• the mixture of the invention is based on the combination of two types of active substances; on the one hand an antiseptic containing at least one alkali metal hypochlorite, and on the other hand, an N-halogenated derivative of one or more molecule (s) of the family of zwitterionic compounds and / or the family of amino acids.
• the inventor has been interested in the characteristics of hypochlorous acid and N-chloramines and in the understanding of the mechanisms involved during ignition in order to develop the antiseptic composition of the invention.
• alkali metal hypochlorite especially potassium hypochlorite and especially sodium (NaOCl) is used since the early 19th century for its antiseptic properties.
• Alkali metal hypochlorite is an alkali metal salt of hypochlorous acid (HOCl).
• HOCl hypochlorous acid
• the title of active chlorine, antiseptic solutions containing hypochlorite sodium, is equal to the sum of the concentrations of HOCl and OCl - (Bloomfield & miles 1979).
• the active form of hypochlorite, hypochlorous acid is a very powerful oxidizing agent that has a very important role in the mammalian defense system.
• taurine In the cytosol of neutrophils, especially neutrophils, an amino acid, taurine, is particularly abundant and, above all, extremely reactive with hypochlorous acid. This reaction gives chloramine taurine. This chloramine is a much less toxic and reactive oxidant than hypochlorous acid and is the most stable of all chloramines (Zgliczynski et al., 1971 & Marquez and Dunford, 1994). Thus, taurine appears to play an important protective role in intra- and extra-cellular media by trapping hypochlorous acid molecules (Cantin, 1994, J. Marcinkiewicz et al., 1998). However, because of its long half-life, chloramine taurine molecules can be transported a great distance from the place where they are formed and exert a significant oxidation and / or chlorination action (Zgliczynski et al. , 1971).
• sodium hypochlorite in aqueous solution, is caustic; it is a non-specific agent capable of hydrolyzing necrotic tissue. This property is due to the presence of sodium hydroxide NaOH.
• the dissolution of tissues is a function of the surface placed in contact with NaOCl (Hand et al., 1978), the contact time and the volume of the NaOCl solution used (Thé et al. . 1979).
• Toxicity is defined as the significant loss of intracellular proteins. This results in a loss of substrate adhesion and cell deformation.
• Alterations in cell viability are measured by the more or less irreversible decrease in mitochondrial activity and thus the cellular respiration essential for energy production.
• Membrane transport systems of TauCl and taurine are independent and both assimilation systems are active and are dependent on temperature, Na + and energy.
• Sodium hypochlorite is a very potent and highly effective anti-bacterial, antiviral and antifungal agent (Shih & al., 1970, Bloomfield & Miles, 1979, Harrison & Hand, 1980). A bactericidal effect on gram- and gram + bacteria was observed, in vitro, up to NaCl concentrations of 3.36 mmol / l (0.025%) (Heggers JP et al 1991). The minimum concentration to kill the HIV virus is 19.062 mmol / l (0.1%) of active chlorine.
• N-monochloramine taurine thus has a very low antiseptic activity, or even zero.
• Inflammation is a defense reaction against any type of aggression.
• the aggressor is detected by sentinel cells, such as macrophages and dendritic cells (DCs).
• DCs dendritic cells
• mediators J. Marcinkiewicz et al., 1999.
• mediators will, therefore, trigger a series of chain reactions in order to activate the immune system, adapt its response to the type of aggression and promote its intervention.
• a healing / repair process will be put in place.
• the cellular component of innate (natural) immunity is composed of monocytes (mononuclear phagocytes), neutrophils (PNN) and natural killer cells (NK). These cells use the complement cascade as a mechanism of primary effector proteins, as well as various recognition proteins such as C-reactive protein and amyloid protein, among others. These proteins are able to bind to the carbohydrate structures present on the bacteria but not on the eukaryotic cells.
• PNNs are part of the first line of defense and are in close cooperation with macrophages, which are major effector cells of the immune system; PNNs are responsible for nonspecific defense in acute inflammation and macrophages have the same role in acute and chronic inflammation (J. Marcinkiewicz et al., 1994).
• T cell receptors and antibodies are recognition molecules.
• B cells recognize carbohydrates, proteins, and some relatively simple chemical structures, whereas T cells only recognize peptides.
• the dendritic cells play a significant role. Under the action of inflammatory mediators, DCs migrate non-lymphoid tissues to the lymphoid organs where they will lose their ability to capture antigens and acquire an increasing ability to stimulate T cells (J. Marcinkiewicz et al., 1994).
• Cytokines are the most important intercellular messenger molecules of the immune system (Megarbane B. et al., 1998). Generated by activated immune cells, they generate specific biological activities, after binding with a receptor on the target cell of the response and this, either autocrine or paracrine manner. Macrophages and T cells are the main cytokine-producing cells, however, many other cells are also able to generate and release them. Cytokines are true regulators of the humoral and cellular immune response. The cytokines work in concert, and the balance between their activities is crucial for the regulation of the immune system. The best known is the competition between TH1 (IL-2, INF-gamma, TNF- ⁇ and IL-12) and TH2 (IL-4, IL-5, IL-10 and IL-13) cytokines.
• TH1 IL-2, INF-gamma, TNF- ⁇ and IL-12
• TH2 IL-4, IL-5, IL-10 and IL-13
• TH1 cells are involved in cellular immunity and are responsible for the cytotoxic activities of macrophages, cytotoxic T lymphocytes (CTL) as well as natural killer (NK) cells.
• CTL cytotoxic T lymphocytes
• NK natural killer
• TH2 lymphocytes are associated with the humoral response.
• IL-10 a TH2 type cytokine, potently inhibits the effective functions of macrophages and TH1 cells (J. Marcinkiewicz, 1997).
• cytokines The regulatory functions of cytokines can be extended to the selection of isotypes of immunoglobulins during humoral response. Thus, selective inhibitions of cytokines result in modulation of the immune response.
• Eicosanoids prostaglandins and leukotrienes
• NO nitric oxide
• Prostaglandins are catalyzed by cyclooxygenase (COX) which converts arachidonic acid into cyclic endoperoxides. There is a constitutive form (COX1) and an induced form (COX2) of COX. The latter is activated in inflammatory cells by pro-inflammatory agents. In macrophages, this leads mainly to the synthesis of prostaglandin E 2 (PGE 2 ) and prostacyclin I 2 (PGI 2 ) and in mast cells to the synthesis of prostaglandin D 2 .
• COX1 cyclooxygenase
• COX2 induced form
• Prostaglandins (particularly PGE 2 ) and leukotrienes (particularly LTB 4 ) modify the immune responses and a balance between the effects of these various eicosanoids allows a smooth functioning of the immune system.
• Nitric oxide is synthesized from L-arginine by both forms of nitric oxide synthetase, the constitutive form, calcium dependent (cNOS) and the induced form, independent calcium (iNOS).
• CNOS is responsible for the synthesis of the basal form of nitric oxide in both the endothelium and the nervous system.
• INOS is found in a variety of cells, including macrophages, neutrophils, and hepatocytes. The generation of nitric oxide plays an important role in the cytotoxicity of macrophages and their ability to destroy invading organisms and thus, in the non-specific defense of the host against many pathogens and against tumor cells.
• NaOCl which has a pronounced bactericidal action, contributes, in the inflammation, to the acceleration of the transition to the debridement phase of the necrotic and purulent masses, stimulates the immunity local and activates the repair process (Lelianov AD et al., 1991).
• the present invention relates to the use of a mixture of at least one alkaline metal hypochlorite and at least one N-haloamine taurine for the preparation of a medicinal product intended, in humans or animals, for the treatment of viral and / or bacterial and / or parasitic infections and / or fungal and / or unconventional transmissible agents (NCTA); and / or chronic, progressive or acute inflammations; and / or for immunomodulatory treatments and / or stimulators of tissue healing; and rinses pre and / or per and / or post surgical, said drug not exerting stimulation of the activity of myeloperoxidase.
• NTA non-haloamine taurine
• the alkali metal hypochlorite is sodium hypochlorite
• the N-haloamine taurine is N-chloramine taurine
• the mixture of the invention is remarkable in that it has very broad spectrum antiseptic properties, anti-inflammatory properties, immunity modulating properties and tissue healing stimulating properties; without stimulating the activity of myeloperoxidase.
• hypochlorite of alacalin metal and N-haloamine taurine are combined in the mixture according to the invention with an excipient, such as purified water, which is suitable for therapeutic use. It is preferably purified water osmosis (isotonic).
• This excipient may contain various agents that are pharmaceutically compatible with alacalin metal hypochlorite and N-haloamine taurine, which makes it possible to modify certain physico-chemical properties (for example: surfactant, oxidative, olfactory or taste properties, stability, pH, pKa, density, solubility, viscosity, color, water-ectanol partition coefficient) of the mixture of the invention.
• the mixture of the invention may also comprise antioxidants and / or amino acids which will have a dilution effect by neutralizing a few molecules alkali metal hypochlorite. These antioxidants, these amino acids and their halogenated derivatives will have a pharmaceutical action either neutral or directed towards the desired therapeutic effects and will not exert direct stimulation, in the presence of the active agents which enter the drug of the invention, of myeloperoxidase activity.
• the mixture according to the invention may be marketed in a form to be prepared before use consisting in mixing the alkali metal hypochlorite (s) with the (s) N-haloamine (s) taurine and one or more excipients.
• This form of presentation may be considered if it is necessary to ensure a better stability in time of the composition and products constituting it.
• the mixture of the invention may be marketed accompanied by an excipient, such as purified water, consistent for therapeutic use. It is preferably purified water osmosis (isotonic).
• This excipient may also contain various agents, pharmaceutically compatible with all the molecules of the final therapeutic mixture, in order to modify certain physicochemical properties of the composition (examples: surfactant properties, oxidizing, olfactory or taste, the stability, pH, pKa, density, solubility, viscosity, color, water-ectanol partition coefficient) by the addition of suitable agent (s).
• agents pharmaceutically compatible with all the molecules of the final therapeutic mixture, in order to modify certain physicochemical properties of the composition (examples: surfactant properties, oxidizing, olfactory or taste, the stability, pH, pKa, density, solubility, viscosity, color, water-ectanol partition coefficient) by the addition of suitable agent (s).
• the alkali metal hypochlorite is sodium hypochlorite
• the N-haloamine taurine is N-chloramine taurine
• the said alkali metal hypochlorite (s) are advantageously presented in the form of a liquid or semi-liquid solution such as a gel, advantageously in an excipient as described below.
• This hypochlorite solution can be stabilized according to the process described in patent EP 0 471 129 A1 by a pH adjusting agent to obtain a pH of between 10 and 10.5 while respecting the cell viability.
• N-haloamine (s) taurine are advantageously presented in the form of a liquid or semi-liquid solution such as a gel, advantageously in an excipient as described below.
• the mixture composition of the invention will be prepared by mixing the two solutions above with at least one excipient such as purified water, conform for a therapeutic use. It will preferably be purified water osmosis (isotonic).
• This excipient may also contain various agents, pharmaceutically compatible with all the molecules of the final mixture, in order to modify certain physico-chemical properties of the composition, (examples: the surfactant, oxidizing, olfactory or taste properties, the stability, pH, pKa, density, solubility, viscosity, color, water-ectanol partition coefficient) by the addition of the appropriate agent (s).
• This mixture is preferably made with an excipient as defined above.
• the derivatives formed will be N-chlorinated, and more particularly N-chloramines.
• hypochlorite titre of the first major active solution should take into account the stoichiometry and reactivity rate of the reaction between hypochlorous acid and Zw / Aam molecules.
• the Zw / Aam molecules that remain should not be stimulators, in the presence of active agents that enter the composition of the invention, the activity of myeloperoxidase.
• excipient or excipients advantageously added during the above processes are useful as a secondary dilution solution in order to be able to perform an adaptive treatment to the different clinical conditions encountered. It is purified osmosis water (isotonic). This excipient will preferably be identical to that used for each of the compounds and mixed derivatives and, if it is not, it will be compatible pharmaceutically to be mixed together, before any use clinical.
• This excipient may also contain various pharmaceutically compatible agents with all of the molecules of the final therapeutic mixture in order to modify certain physicochemical properties of the composition (examples: surfactant, oxidizing, olfactory or taste properties; stability, pH, pKa, density, solubility, viscosity, color, water-ectanol partition coefficient) by the addition of the appropriate agent (s).
• This excipient may contain anti-oxidants and / or amino acids which will have a dilution effect by neutralizing the oxidants of the main active solution and especially the alkali metal hypochlorite.
• antioxidants, these amino acids and their halogenated derivatives will have a pharmaceutical action either neutral or directed towards the desired therapeutic effects, while having a lower toxicity than the oxidants of the main active solution. In all cases, they must be compatible, pharmaceutically, with the compounds and derivatives used in these processes.
• the mixture according to the invention may be in any form suitable for local application, such as a gel or an aerosol.
• the invention is particularly interested in the local treatment of infections due to viruses of the family of herpesviridiae.
• the mixture of the invention is advantageously used locally to avoid side effects, such as increased risk of atherosclerosis. It can be applied to all external or internal mucosa, buccal, genital, vaginal, ophthalmic, otic, sinus, rhinogenic, dermal, etc.
• the mixture of the invention may be in any form suitable for this administration and preferably in a semi-liquid form, preferably a gel by the addition of one or more pharmaceutically compatible substances, such as cellulose, or amino acids, peptides and / or proteins.
• composition of the invention may also be adapted to the clinical conditions and / or the mucous membranes. This adaptation is done by modifying the concentrations of active products of the therapeutic solutions.
• antioxidants specifically trapping NaOH is recommended.
• the mixture according to the invention is useful for the local treatment of chronic and / or progressive and / or acute inflammatory diseases or processes. It is also indicated for the pre and / or per and / or post-surgical rinsing of the internal and / or external mucosa and open wounds.
• the invention particularly relates to a method of treating the lesions and conditions described above consisting in contacting the mucosa to be treated with the composition of the present invention, for example (ENL) for a period of about 20 to 60 seconds , with a dosage of 2 to 3 applications per day and not followed by rinsing.
• the amount of composition employed should be sufficient so that the therapeutic active agents are not all neutralized in one way or another.
• the contacting should not remain static.
• the concentrations of the solution should be adapted to the evolution of the clinical situation until the cure of the disease.
• the invention particularly relates to the local treatment of lesions and infections related to chronic and / or acute periodontitis.
• the composition of the invention is remarkable for being used in irrigating the bottom of the periodontal pockets in order to eradicate these periodontal pockets thanks to its antiseptic, anti-inflammatory, modulating actions. immunity and stimulator of healing on periodontal tissues (alveolar bone, alveolar-dental ligament and gingiva).
• Chronic periodontitis is a disease that is mainly due to the pathogenic action of anaerobic bacteria, particularly Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Bacteroides forsythus and Prevotella intermedia. These bacteria cause a chronic inflammatory process that results in the gradual destruction of the periodontium (tooth support tissue). The term of this disease is the loss of the tooth (odont) following the disappearance of the supporting bone tissue.

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• 2001
  • 2001-01-23 FR FR0100862A patent/FR2819723B1/fr not_active Expired - Lifetime
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  • 2002-01-16 AT AT02711967T patent/ATE358474T1/de active
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  • 2002-01-16 DK DK02711967T patent/DK1401422T3/da active
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